Preparation of mono-alkyl or-aralkyl cyanoacetic acid esters



Patented Oct. 13, 1953 PREPARATION OF MONO-ALKYL OR -ARALKYL CYANOACETIC ACID ESTERS Arthur C. Cope, Belmont, Mass., assignor to Merck & 00., Inc., a corporation of New Jersey N Drawing. Application March 1, 1949, I Serial No. 79,115

8 Claims.

This invention relates to an improved process for preparing mono-alkyl or -aralkyl cyanoacetic alkyl or aralkyl esters, including both the primary and the secondary derivatives, from aliphatic or aromatic or aliphatic aromatic ketones or aliphatic or aromatic or aralkyl aldehydes, by reacting such ketone or aldehyde with an alkyl cyanoacetate in the presence of a condensing agent and under reduction or hydrogenation conditions.

The process of the invention may be illustrated by the following equation:

R R H H wherein R is selected from hydrogen and alkyl, aryl and aralkyl radicals; and R1 is selected from alkyl, aryl and aralkyl radicals; and R2 is selected from alkyl and aralkyl radicals.

The process is of particular advantage'for the production of the mono-alkyl cyanoacetic esters in which the mono-alkyl group is lower as well as higher alkyl as the hexyl, heptyl, octyl and the like radicals, and even higher, including both straight and branched chain alkyl. In general, the mono-alkyl or -aralkyl derivatives resulting from the procedure are saturated in the aliphatic portions thereof and without any hydrogenation of any benzene radicals which they may contain.

A wide range of ketones may be condensed with cyanoacetic esters in accordance with-the present invention, including open chain ketones, such as acetone, methylethyl ketone, methyl-n-propyl ketone, methyl-n-amyl ketone, di-n-propyl ketone, mesityl oxide, diethyl ketone, and the like, as well as cyclic ketones, such as cyclohexanone, cyclopentanone, and the like, and aryl ketones, such as acetophenone, propiophenone, butyrophenone, and the like.

A similar wide range of aldehydes may be condensed with the alkyl or aralkyl cyanoacetic esters, including open chain aldehydes, straight or branched, such as acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, heptaldehyde, as well as cyclic aldehydes as cyclopentylaldehyde, oyclohexylaldehyde and the like, and including aryl aldehydes such as benzaldehyde and the like.

The alkyl or aralkyl radical (R2 above) in the cyanoacetic alkyl or aralkyl ester starting material may be any suitable alkyl group such as hereinabove indicated for the other alkyl groups and advantageously a lower alkyl group, or any suitable aralkyl group as benzyl, and the like.

In general, the invention includes the reaction when carried out in the presence of a suitable condensing agent consisting of a soluble salt, advantageously a soluble salt of a nitrogen base (which may be primary, secondary, or tertiary), i. e. an ammonium or amine base or an alkali metal salt of an organic acid, or an acid amide, such as acetamide. Preferably, the salts which are used are the acetates of the bases, such as diethylamine acetate, monoethylamine acetate, triethylamine acetate, ammonium acetate, piperidine acetate and the like. Compounds or condensing agents which have been found to have important advantagesfor carrying out the condensation are the acetates of primary or secondary amines, or even tertiary amines particularly with the aldehydes, or ammonium acetate, which enable the condensation to be accomplished with particularly good yields of the desired product in fairly pure state and with a minimum of side reactions, polymerization, etc. Ammonium acetate, on heating, is converted into acetamide. This substance, which may be formed in situ in certain of the reaction mixtures in which ammonium acetate is used as the catalyst, is in itself a good catalyst for these reactions, and may be introduced directly into the reaction mixture to effect the condensation; or, solutions of soluble salts.

in acetamide may be used with advantage.

In this specification and the appending claims, I the expression an ammonia base is used in its generic sense to embrace ammonia or ammonium hydroxide and the primary, secondary, and tertiary amines, as referred to at lines 10-12 above, and when the term amine is used without the specific modifying adjective, primary, secondary, or tertiary, the term is used in its generic sense embracing all three forms.

The process of producing the mono-alkyl or -aralkyl cyanoacetic alkyl or aralkyl esters may comprise having together in the reaction mixture solely (1) a ketone or an aldehyde, (2) a cyanoacetic alkyl ester, (3) a condensing agent .and (4) a hydrogenation catalyst while simultaneously introducing hydrogen as a reducing the reaction conditions in which they are emagent, or the reaction mixture may also contain ployed in that they exercise solely the property an organic acid, such as the organic acids of the of a solvent and vehicle for the reactants but do acetic acid series, for which purpose acetic acid not enter into the reaction so as to contribute is particularly important. In place acetamide 5 a substituent group in the reaction products. in such an acid solution, other amides and other The invention may be illustrated by, but not soluble salts may be used, with improved results restricted to, the following procedures exemplifyas compared with the use of such soluble salts ing the application of the method to each of the and amides alone. When the reaction is carried three classes referred to in the preceding paraout in the presence of an acid such as acetic acid, graph: an additional solyent, such as benzene or other A, Lowe o lewldr ali hati aldehydes inert solvent may be used. 01' the acid it e f may with ethyl cyan'o acetate.A mixture of 56.6 be used as the solvent. As indicat d abo grams (0.5 mole) of ethyl cyanoacetate, and 0.6 eve it s not s ary h an ac d b used fndle 01' the freshly distilled selected lower molecthe reaction medium, as the reaction will also lsulan weight aliphatic aldehyde, and 1.0 gram 0! Proceed ut e e t 94 1i; orthejs lv t; palla zed charcoal and 80 cc. of glacial acetic or, if desired, the inert solvent alone may be added acid Wi'sfilcddfin a 500 cc. Pyrex bottle (with to the reaction medium. an arrangement for permitting hydrogenation), Vari u a y Particularly a hydrogenation and to mixturewas added a solution or 2 cc. atalyst havin an a ivity a u't't e sam a tliatzo (0."02ihol) ofpi' 'cridinc in 200 cc. of glacial of m ta of the platinum and pa ladi m. acetic hydrogenation at a pressure of 1 including catalysts selected from" the groupie? toga. atmospheres was begun immediately. Reme 0f the Platinum and P m amily. duction was rapid and exothermic. In 1 to 3 such as a noble metal ata yst s p a um an hoi'irs't'he theoretical amount of hydrogen (0.5 Palladium eetalysts y H u for the y mole) was taken up andabsorption ceased. The enatl n. I h s specificatio and t appending resulting individual ethyl alkylcyanoacetates were laim as, ind a d j he p e d t e. isolatedby'filter ing the reaction mixture, adding the xpr s n hyd ena i n a a yst hav 50 cc. 'oibenzene to the filtrate-and washing'the an activity about thesamea hat Of metals, resulting solution with two50 cc. portions of l0% he. P a and pa la um i includes sodiumcllloride solution followedby three 25 -00. wlthlnthe s op of hydrogenation ata portions oi -water. Wherever an emulsion formed hraee byzt e quoted exp es o o metals at t'iiis point, it was broken by-theadditionot-a otthe p a u and palladium family. A ca a few cc. or. ether. Thecombined washings werewhichils part u a y advantageous for the hyextracted w'itli two small 3 portions or drosena ion s ad u uppor edo eha which were then combined with the original ben- This catalyst may be prepar or xam e. zene solution; and the combined benzene solutions azltatinaa powdere c a coa lloh s re p were distilled throu h a" Widmer column under mal char oa w h a a eo so tlon.. of; al s reduced pressure. No ethyl cyanoacetate was rediima l i e a t osphereoth dr seng covered intheforerun, and the individualetlwl inta lepropo is. a out. z t of pa l d um. 4o alkyl cya'noacetate was recovered and only a small chloridetofipart o h rcoa sl o sll l dr distillation residue remained, the ethyl alk lc belcontinued until the palnf hlor e 7. anoacetate. beingrea'dily purified -by.distillation.. duced, and, the. pal d u DOS d. on h Whenaldolwasemployed asthe starting.- aldev. har l- 'T co l t a then e lofiwnvdc, on -mo1e-o hydrogen were. absorbed and-- washed and dri d. is h n. ad me 55.5 grams (66%) oil-ethyl n-butylcyanoacetatel diate usein the process, or it may be kept inf was obtainedh ve'cllo Over-sulfuric acid t la This catalyst 3;. Branched chain, higher. molecular. weiaht may be used with advantage aliphatic .aldehydes -a1ld.benzaldehyde. A..mixi-. While inthe broad-aspect, the reaction condit 55 grams 0 5 1 1 of eth l Hons-are generally substantially the. same with, tatefandpofi moleofjhe selected aldehyde; es themarbonylbompound'(ketone 6.0. grams (0.05 mole). glacial acetic acid. and 1506 dehydel tart n 'm al seleetedythe optimumcc..oi.dioxane (purified by boilingover sodium, experimental conditions f r e ti for'ABhours and redistilling) was placed in a5007= subtly-acco ding to e ype of carbonyl com:v cc..,Pyrex. bottle, asin ExamploA, and cooled in. ound used- For example, in'the examples l w an.ice salt mix'tureto 4?. C. 2.0 00.- Om mole) which illustrate the react on in' the presence oi a'. piperidine was added drgpwise t t mixture solvent, 'piperidine"' acetate and acetic acid were duringapproximatel-y .10 minuteswith. occasional employed with particular effectiveness witth the v Swirling, The mmpgrature. e ,205 and t e yd s'; and ammonium acetate and acetic ccldi solutiombecame .turbid. When the addition was was wltli'the k'e'to'nes." When ethyl 'cyanoaeecomplete,. 1.0? gram of .palladinized-charcoal was tate'was reacted 'withketo'nes, alcohol 's'erved'a's a added. and the mixture was hydrogenated'as in most'satisiactorysolvefit foruse in'carryin'gout the'fprec'ding example, w tnm indicated tno'proces's'of the invention." Dlox'an'e ser'ved mo i iphatic'aldehydes heat was evolved and reduction-- satisfactorily as 'asolventinreacting ethyl cyan g, was complete-in about hours. With ben'z'aldeacetate with higher aldehydes (e. g". 'isobutyraldefi mule/hydrogen absorption was iairly- -slow-even-- yde,'lsov'aleraldehyde.heptaldehyde and ben'zal when the reaction wascarried out at 60- C The dehyde) with 'gIa'cial'acetic' a'ci'd' serving" as a; ter wr' i l te; ahd junfipd flsmtheprm most "satisfactory solvent wlicn reacting the lower ing example Inkth'e caseof the indicated almolecular weight aldehydes'fas acetaldehyde, p'ro' iphatlc aldehydes, methyl cyanoacetate was re pionaldehydearid butryaldehyde Alloi such s01- 7 c0v'ered', -and only small'distillation residues; were 1 vents are generically aliphatic oxygenated sol}; left;-' With-bnz'aldehydethere wasaforerun or vents. Thealiphatico iygenated (that is,oxy genethylcyanoacetate 8.il "gramsl'and appreciable containing substance) solvents, for example, the residue '35 grams):} acetlcacidalcohol, and dioxarie' rei erred'to above, C'.- Aliphatic ket0nes.-56.6 grams oi ethylcyare suitable solvents because "they are inrtunder anoacetate (0.5 mole), and 0.55 mole of the sclected ketone, and 3.9 gramsoiaminonium acetate (0.05 mole), and 6.0 grams (0.1 mole) or glacial acetic acid, and 100 1.0 gram of palladinized a 500 cc. Pyrex bottle and hydrogenated as in the preceding examples. The reactions with the ketones were also exothermic but to a lesser de' gree than with the aldehydes of the preceding examples. The esters were isolated and purified as in Example A.

While the dioxane and the ethanol employed respectively as the solvent in the preceding Examples B and C were each used along with glacial acetic acid, just as glacial acetic acid was used alone as the solvent in the preceding Example A, thus either the dioxane or the ethanol may like wise be used alone as the solvent as illustrated by, but not restricted to, the following examples:

D. Aliphatic ketOne with dioxane.-To a solution of 22.6 gram (0.2 mole) of ethyl cyanoace-j tate, 17.4 grams (0.3 mole) of acetone, and 0.3 grams (0.004 mole) of ammonium acetate, in "30 cc. of dioxane in apparatus as in Example A, there was added on gram of ten per cent palladinized charcoal catalyst, and the mixture was shaken with hydrogen at room temperature until one molar equivalent of hydrogen was absorbed, which occurred after three hours and under six hours. The reaction mixture was filtered and the filtrate distilled giving a yield of 22.1 grams (87%) of ethyl isopropylcyanoacetate boiling at 98.5 C. at 10 mm.

E. Aliphatic ketone with ethanol.-To a solution of 22.6 grams (0.2 mole) of ethyl cyanoacetate, 17.4 grams (0.3 mole) of acetone, and 0.3 grams (0.004 mole) of ammonium acetate, in 30 cc. of ninety-five per cent alcohol in apparatus as in Example A, there was added one gram of ten per cent palladinized charcoal catalyst, and the mixture was shaken with hydrogen at room temperature until one molar equivalent of hydrogen was absorbed, which occurred after one hour and under six hours. The reaction mixture was filtered and the filtrate distilled giving a yield of 23.6 grams (93%) of ethyl isopropylcyanoacetate boiling at 98.5 C. at 10 mm.

The following procedure exemplifies the method of producing the mono-alkyl or -arall yl cyanoacetic alkyl or aralkyl ester in which no solvent .is used in the reaction medium:

F. Reaction mixture containing no slve1tt. 56.6 grams (0.5 mole) of ethyl cyanoacetate, 32 grams (0.55 mole) of acetone, 3.9 grams (0.05 :mole) of ammonium acetate, 1.0 gram of palladitnized charcoal catalyst were placed in a 250 cc. Pyrex .bottle and hydrogenated at a pressure of one to two atmospheres. After about six hours hydrogen absorption ceased. The catalyst was sepatrated by filtration and washed with 50 cc. of benzene. The water formed in the condensation- :reduction (8.5 cc.) was separated from the benrzene solution, which was then washed with :sodium chloride solution, water, and distilled :under reduced pressure. The distillate was washed with dilute hydrochloric acid and water and redistilled, and yielded 56.8 grams (73%) of ethyl isopropylcyanoacetate, B. P. 86 (5.5 mm), "70 (2 mm.) n 1.4203.

The ethyl monoalkylcyanoacetates obtained according to the preceding examples are represented by the formula RCH(CN)COOC2H5, in which R represents the alkyl group attached as a result of the method of the invention to the 'methylene carbon of the starting ethyl cyanoacetate, and are identified by the alkyl group in cc. or 95% ethanoland charcoal were placed in the'following table, which also includes the ketone or aldehyde used as starting material:

ACCORDING TO PROCEDURE OF EXAMPLE A K t m h d lieac- Boiling pt. e one or a e y e on Alkyl group R used in preparation time (hrs.) 0. Mm.

Ethyl Acetaldehyde 2.5 84- 85 7 n-Propyl Propionaldehyde. 96 8 n-Butyl Butyraldehyde 1.3 108-109 8 ACCORDING TO PROCEDURE 0F EXAMPLE B IsbbutyL... Isobu'tyraldehyde 4 9s- 99 7 Isoamyl Isovaleraldehyde. 4 113-114 7 n-Heptyl. Heptaldehyde 4 11l-1l3 1 Benzyl Benzaldehyde 16 118-122 4 ACCORDING TO PROCEDURE OF EXAMPLE 0 Isopropyl Acetone 6-6 89- 91 8 Sec. butyl Methylethyl ketone-.. 4. 5-6 99-100 7 l-methylbutyl... Methylpropyl ketone 11 lllll2 8 Oyclohexyl Oyclohexanone 138-139 8 1,3-dimethyl- Methylisobutyl kebutyl tone 8-1l 117-119 8 l-methylhexyl Methylamyl ketone--. 9 -137 8 4-heptyl Dipropyl ketone 7-22 l31-132 7 1-n1ethylheptyl Mcthylhexyl ketone... M 112-115 1.0

In the preceding table, the products resulting from using heptaldehyde, methylisobutyl ketone, methylamyl ketone, and methylhexyl ketone as the carbonyl compound starting material are new compounds suitable for use as intermediates for other chemically useful substances.

While the invention has been illustrated by the above specific procedures involving the use of piperidine and ammonium acetate as the con densation catalyst, other nitrogenbases or ammonium salts of organic acids, particularly the salts of nitrogen bases, with or without acetic or other acids, may be used with advantage. In general, the effectiveness of a salt as a condensing agent or catalyst in the process of the invention depends to a reasonable measure upon its solubility in the reaction mixture. Condensation catalysts which are typical of those used in accordance with the invention and which may be used with. advantage are ethylene diamine diacetate, diethanolamine acetate, aniline acetate, piperidine butyrate, piperidine oleate, diethylamine acetate, glycine,.sodium acetate, and potassium acetate, and the like.

This application is a continuation-in-part of my copending application Serial No. 26,244, filed May 10, 1948, now abandoned, which in turn was a continuation-in-part application of the then copending application Serial No. 539,174, filed June 7, 1944, now abandoned.

While the invention has been demonstrated in relation to certain specific embodiments of it, it is understood that other suitable variations, modifications and substitutions may be made in it withwherein R is a member of the group consisting of hydrogen, an alkyl and the phenyl radical, and R1 is a member of the group consisting of an alkyl and the phenyl group, (b) a cyanoacetic alkyl ester, (c) an ammonia-derivative condensing agent which is a member ot-the mupeomistml o! acetamide, ammonium acetate, and a fatty acid salt 01 a nitrogen buaiinwhltilibflflfi a y radical'attached to the nitrogeniehydrocarbon, witha total of no more than six carbon atoms in all of said hydrocarbon). and a hydrogenation catalyst which is a member of the group conanoacetic alkyl ester in said reac ion mixture while simultaneously introducing hydrogen as a reducing agent; and thereafter recovering theend product sought.

2. The process as claimed in claim 1, wherein an inert organic solvent in which is phatic oxygen-containing advent.-

3. The process of producing a member ofthe ins o momra kyi. and, -aralkyl cyanoacetic alkyl andaralkyl esters, which. pr cess comprises having together in a reaction mix ture (a) a carbonylv dthefonnula.

wherein R is a member of the crow. consistingef hydrogen, an alkyl and the phenyl radical, and R1 is a member of the group consisting of an alkyl and the phwyl gmup, (b) a cyanoacetic alkyl ester, an acetate of an amine (in which any radical attached to the nitrogen is hydrocarbon with a total of no mime 322181131X carbon atom.-in all of said hydrocarbon). and pa ladium as a hydrogenation catalyst: and allowmg the car.- bonyi compound tawnlanae-with theicyanmcetic alkyl ester in said meactim mixtumin the-westhe acetate of an mine is piperidinezwetate.

5. The process ofv wproducing ibutyiecamacetic ethyl ester, which-comprises having together in a reaction mixture hutyraldehyde,- cyanoacetic ethyl ester, pineridine msetfltflpall intglwml acetic acid, and palladium onacarrier, V the aldehydeto condemeliwith the cyanoacatic ester while esimultaneously'introducing hydrogen as =a reducing agent; .andthereatter recovering the end product caught- 6. 'The processot producing benzyhcyanoacetic ethyl ester, which compriseahavingtogetmr in a reaction mixture 'benzaldehyde, cyanoaoetic ethyl eaw'mincr dmaaeetata ail melamine, and paliadmm on a. carrier. and aiiowina the aldehyd to eondense with the cyanoaoeticester in said reaction mixture in the presence 01 glacial acetic acid while simultaneously introducim hwdmaen a amucma agent: and W1:lltfl"Wi I the ondporchict'soughtr '1. The. process. 0! produdnla :mnnccmisting of monoaikyi, noacetic alkyl and aralkyl esters. which places! cmmuifl harm: together ina reaction mixture (oi a-carbonyl command of the Ionnula wher in R is a manh nt-the s oupcennatinl 0! intone. an alien; and the ohm adi al. an R1 isamembe o! the group a an 11m and t e phw a o n- Q. a exanoacet (c) ac tate... an i ne lad um ail-:11hyd senationcataiyet; a d al ow in th carbony command t ond ns th cyanoacet cwa kyl e te in sai e ction :mixtu e in the of glacial acetic acid :while simultaneoiw y. troduci h d zen as a educ n amt; and the eafte eco e i t e end Pm!! uatseu h 8;- ;Ihe pro as 'p ducinc c hex wyaao amti eth ster. wh h marin havim to what in a eact on m x ure c ohexe one. ,cyanaemic ethyl e ter, a tat a in glacial acetic acid, and palladium on a carrier a5 .a h dr enation catalyst, and allow g the cyclohexano a t condense with the qya wt eat aw ilesim fl ane usl intr ducin yd gen a: a reduc naesen thereafter recover ng the :end :product sought.

0. cops.

0 .B ehrpnoei Cited ,in the his OfthiS patent UNITED STATES PAIEN'IS 

1. THE PROCESS OF PRODUCING A MEMBER OF THE GROUP CONSISTING OF MONO-ALKYL AND -ARALKYL CYANOACETIC ALKYL AND ARALKYL ESTERS, WHICH PROCESS COMPRISES HAVING TOGETHER IN A REACTION MIXUTURE (A) A CARBONYL COMPOUND OF THE FORMULA 